Stress can be defined as an environmental transient challenging homeostasis. Most organisms have developed "stress responses" that buffer the stress or attenuate its effects. Examples include the sporulation of bacteria and the estivation of amphibians. Perhaps the best known and least understood stress response in mammals is activation of the hypothalamic-pituitary-adrenal (HPA) axis. The mechanism by which the hypothalamus stimulates the pituitary POMC cells to secrete ACTH and other POMC products, the role of these products, and the role of the consequent adrenal glucocorticoids in responding to stress is poorly understood. This program project has three objectives. The first objective is to better understand the array of hypothalamic hormones regulating the pituitary POMC cell and the biochemical mechanisms by which this regulation occurs. The second objective is to better understand the stress related biologic effects of the specific molecular elements of the HPA response to stress. The third objective is to more precisely characterize the HPA response to stress in the human being and to define its role in several "stress associated" disorders of growth and development. To accomplish these objectives we have developed five interacting projects using five shared facilities. The shared facilities include tissue culture, radioimmunoassay, transgenic mouse, histochemistry and administrative "cores".